Background/Introduction

The concurrent use of cisplatin or cetuximab with radiation (RT) has been shown to improve survival of patients with locally advanced stage III-IV head and neck squamous cell carcinoma.

A meta-analysis examining the addition of Cisplatin-based chemotherapy to RT in the definitive setting found an absolute benefit for chemotherapy of 6.5% at 5 years, when given concurrently. (Pignon, Radiother Oncol. 2009)

The addition of cetuximab to RT led to improvement in 5-year overall survival in a Phase III trial, from 36.4% to 45.6% in the cetuximab plus RT group. (Bonner, Lancet Oncology, 2010)

In patients with recurrent or metastatic head and neck squamous cell carcinoma, the addition of cetuximab to chemotherapy alone improves OS with a HR of 0.8. (Vermorken, NEJM 2008)

RTOG 0522 was designed to test the hypothesis that adding cetuximab to RT with concurrent Cisplatin for front-line therapy for locally advanced head and neck cancer would improve progression-free survival (PFS).

Methods

This was a Phase III randomized controlled trial.

It enrolled patients with Stage III and IV squamous cell carcinoma of the oropharynx, larynx, and hypopharynx.

Adherence to RT was high. There were some major deviations but these occured for less than 10% of patients.

Adherence to cisplatin was high with over 90% of patients receiving the planned 2 cycles

However, 26% of patients randomized to cetuximab received less than 6 weeks of the prescribed drug.

Progression-free survival (PFS): There was no difference in PFS between the 2 arms (HR 1.05, 0.84-1.29; P=0.66). The 2-year PFS rates were 64.3% for the Cisplatin arm and 63.4% for the Cis +Cetux arm.

Overall survival: Likewise, there was no difference in OS (HR: 0.87, 0.66-1.15; P=0.17). The 2-year OS rates were 83% for the Cis + Cetux arm vs. 80% for the Cis arm.

There were no differences in the patterns of failure.

Acute toxicity:

2% of patients died within 30 days of completion of therapy within each arm.

There was more acute mucositis and skin reaction within the radiation portal in patients receiving cisplatin + cetuximab.

Rates of Grade 3/4 mucositis were 33% in the Cis arm and 43% in the Cis + Cetux arm.

Rates of Grade 3/4 in-field skin reaction were 15% in the Cis arm and 25% in the Cis +Cetux arm.

Long-term toxicity: there was no difference in the rates of dysphagia between the 2 groups.

Treatment effect by p16 status:

321 samples (51%) were evaluable for p16 status, and

73% of oropharyngeal tumors were p16+.

Among oropharynx patients with p16+ tumors (N=235), there was a trend towards improved PFS in patients treated with Cisplatin alone, although this did not reach significance. Otherwise there were no apparent interactions between p16 status and PFS according to receipt of cetuximab.

Authors’ Conclusions

Adding cetuximab to chemoradiation with Cisplatin did not improve PFS or other endpoints.

The addition of Cetuximab was associated with 10% higher in-field grade 3-4 skin reaction and mucositis.

There was no increase in persistent dysphagia.

There does not appear to be a differential effect by p16 status.

However, longer follow-up is needed to verify the secondary findings.

Why did cetuximab fail in this setting? Two possible explanations:

Cetuximab and Cisplatin have similar mechanisms of action, so there is no synergy as far as radiation sensitization.

The intensity of Cetuximab used in this study is too low to yield a systemic effect.

Combining Cetuximab with agents that have different mechanisms of action, such as taxanes.

Adding Cetuximab to multi-agent neo-adjuvant chemotherapy regimens.

Clinical/Scientific Implications

This study indicates that there is no benefit to adding Cetuximab to Cisplatin-based chemoradiation in the definitive treatment of locally advanced head and neck squamous cell carcinomas.

It is unfortunate that this study did not include a third arm, as initially planned, of RT + cetuximab, as this may have helped answer one of the more interesting questions: how does chemoradiation with Cisplatin compare to RT with Cetuximab, and is there a differential treatment effect depending on p16 status?

It is also unfortunate that p16 status was only able to be assayed in ½ of tumor specimens, as the p16 subset analysis was underpowered in this study.

Despite being underpowered, there is an interesting suggestion that among p16+ oropharynx patients, there was a trend towards improved PFS with Cisplatin alone compared to chemoradiation with Cetuximab.

This lends support to some emerging data that HPV+ patients may not benefit from cetuximab as much as they do from Cisplatin, and therefore that HPV status and EGFR expression may be mutually exclusive. If so, Cetuximab may actually provide greater benefit for HPV- patients.

The impact of EGFR inhibition in the context of HPV+ disease needs to be evaluated in a more rigorous fashion, and the RTOG 1016 study (RT + Cis versus RT + Cetux) will likely be an invaluable guide in the definitive management of patients with locally advanced squamous cell carcinoma of the head and neck.